The specific aims of this research are: (a) to purify and characterize the properties of the thyroid stimulating immunoglobulins-G (TSI) of Graves' disease, (b) examine the kinetics of the interaction of TSH and TSI with receptors in isolated human and mammalian thyroid cells, plasma membranes and artificial vesicles, (c) examine the physiochemical nature of TSH and TSI receptors in isolated thyroid cells, plasma membranes and artificial vesicles containing the receptors, (d) study the interaction of thyroglobulin, solubilized thyroid microsomal antigen, and immune complexes with orbital muscle, (e) continue clinical studies which correlate immunologic and pathologic phenomena with the onset, maintenance, or remission of clinical manifestations of Graves' disease and the complications of ophthalmopathy and pretibial myxedema, (f) study in man genetic determinants of thyroid disease incidence and of thyroid autoantibody production. Human TSH-receptor and adenyl cyclase will be isolated by affinity chromatography. The former will be solubilized and incorporated into artifical membranes. The binding of TSH and TSI to such membranes will be selectively modified by the introduction of lipids. Conditions optional for isolation of TSI will be defined. Attempts will be made to isolate orbital muscle receptors for thyroglobulin and thyroglobulin-antithyroglobulin immune complex (TgA) by affinity chromatography. TgA will be measured radiometrically in the serum of patients with Graves' disease and healthy controls. The fate of TgA will be studied by radioisotopic thyroidolymphography. Immune sera will be obtained by immunizing animals against human lymphocytes possessing specific lymphocyte-defined histocompatibility antigens from Caucasians and Japanese subjects in an attempt to discover an antigen common to both ethnic groups. Patients with Graves' ophthalmopathy and orbital pseudotumor will undergo orbital ultrasonography and supervoltage orbital irradiation.